Extracellular nucleotides have been implicated in a number of physiological
functions. Nucleotides act on cell-surface receptors known as P-2 receptor
s, of which several subtypes have been cloned. Both ATP and ADP are stored
in platelets and are released upon platelet activation. Furthermore, nucleo
tides are also released from damaged or broken cells. Thus during vascular
injury nucleotides play an important role in haemostasis through activation
of platelets, modulation of vascular tone, recruitment of neutrophils and
monocytes to the site of injury, and facilitation of adhesion of leucocytes
to the endothelium. Nucleotides also moderate these functions by generatin
g nitric oxide and prostaglandin I-2 through activation of endothelial cell
s, and by activating different receptor subtypes on vascular smooth muscle
cells. In the heart, P-2 receptors regulate contractility through modulatio
n of L-type Ca2+ channels, although the molecular mechanisms involved are s
till under investigation. Classical pharmacological studies have identified
several P-2 receptor subtypes in the cardiovascular system. Molecular phar
macological studies have clarified the nature of some of these receptors, b
ut have complicated the picture with others. In platelets, the classical P-
2T receptor has now been resolved into three P-2 receptor subtypes: the P-2
Y1, P-2X1 and P-2TAC receptors (the last of these, which is coupled to the
inhibition of adenylate cyclase, is yet to be cloned). In peripheral blood
leucocytes, endothelial cells, vascular smooth muscle cells and cardiomyocy
tes, the effects of classical P-2X, P-2Y and P-2U receptors have been found
to be mediated by more than one P-2 receptor subtype. However, the exact f
unctions of these multiple receptor subtypes remain to be understood, as P-
2-receptor-selective agonists and antagonists are still under development.